1. Field of the Invention
The present invention in its simplest form is a container for freeze-drying and storing pharmaceutical material. In its more expanded form it serves to collect, process, freeze-dry, store, reconstitute and utilize biological and/or pharmaceutical material solutions preferably under sterile conditions. In one preferred form the container can be collapsed to accommodate the volume of the freeze-dried product during storage and expanded to the volume corresponding to the rehydrated product. Hereinafter, the use is made of blood products, and the special needs associated with such product, as the lyophilized product is for description purposes and by no means should be taken as a limitation of the invention.
2. Description of the Related Art
Lyophilization is used to increase the shelf life of biological/pharmaceutical solutions by freezing the solution and then removing the solvent (usually water) by applying high vacuum. The rate of lyophilization is dependent on the vapor pressure of the drying mass, which in turns depends on the heat transferred by conduction from the shelf of the lyophilizer to the top of the frozen mass where evaporation occurs. The dehydrated frozen mass, or cake, is then stored until it is reconstituted by adding a solvent similar to that removed and then used as intended.
U.S. Pat. No. 4,973,327 of Goodrich et. al. of Cryopharm Corp discloses many of the desirable features of the present invention as described in the Abstract: xe2x80x9cA lyophilization bag is provided in which a fluid, such as blood, may be introduced, lyophilized without collapsing the bag, stored, reconstituted and distributed from the bag without intermediate transfer of the useful contents from the bagxe2x80x9d.
U.S. Pat. No. 5,257,983 discloses a container with its flexible peripheral walls reinforced with rigid structures to prevent its inward collapse and a bottom wall made of a rigid material. Samples of the last containers made by Cryopharm (obtained from Dr. Goodrich) were square rigid trays 1xe2x80x3 high 10xe2x80x3xc3x9710xe2x80x3 made of polyester film 0.020xe2x80x3 thick.
Bergmann""s U.S. Pat. No. 5,309,649 discloses xe2x80x9ca container for freeze drying materials under sterile conditions, wherein the sides of the container consist at least partly of a hydrophobic, porous, germ-impermeable, water vapor-permeable membrane.xe2x80x9d Two forms of the container were described: a bag and a rigid rectangular tray both covered with the membrane. In 1995 W. L. Gore introduced the Lyoguard bag, a single-use sterilizable processing bag providing a protective barrier before, during and after bulk freeze drying (Flyer #LP001:03/08/95 and a brochure from W.L. Gore and Associates, Inc. Microfiltration Technologies Group, Elkton Md.) that looks very much like that shown by FIG. 2 of ""649. The bag described by Pat. ""649 and Gore""s bag are open along one entire side to allow product introduction after which the open side of the bag is heat-sealed. Further, both are made with two layers, a floor and a roof, with the roof incorporating a hydrophobic membrane. Neither have sidewalls. Pat. ""649 also illustrates a tray covered with a hydrophobic membrane, described as a xe2x80x9c . . . trough (tray) consists of liquid-impermeable synthetic resin and preferably has a wall thickness of 0.5 to 1 mmxe2x80x9d (i.e. 0.020 to 0.040xe2x80x3 thick).
U.S. Des. Pat. Nos. D430,939 and D425,205 and resulting Lyoguard tray (W.L. Gore and Associates) illustrate a rigid wall container topped with a hydrophobic membrane with a flexible, transparent, thin-film bottom that closely conforms to the lyophilizer shelf for more efficient heat transfer. It also incorporates a large top port positioned above the floor of the tray.
Each of the prior art containers suggests useful features yet all can be improved. There are no prior art containers that provide a simple collapsible container having a flat bottom that conforms to the shelf of the lyophilizer or that provides the rectangular shape so useful for lyophilization. Some collapsible tray-shaped containers are complicated and require additional steps to receive and remove reinforcing members that allow the container to collapse or maintain its shape during lyophilization. Other trays used for lyophilization have a relatively heavy wall that results in at least two factors that reduce heat transfer between the shelf and the product. First, the thicker the floor of the tray, the greater the resistance to heat transfer. Second, and more importantly, it is almost impossible to maintain the bottom of a rigid thin plastic tray completely flat against the shelf of the lyophilizer. Though the product to be lyophilized weighs down the bottom of the tray downward towards the shelf, the weight of its thin layer (usually less than 10 mm) is insufficient. Thus, a bottom made of a noncompliant material will result in a non-conforming floor with some sections lifting off the shelf preventing said sections from having intimate shelf contact causing inefficient and non-uniform heat transfer. The latter, may result in non-uniform lyophilization of the product, which can lead to a final, less viable end product. Certainly, poor heat transfer would slow down the freezing and the warming of the product required for the process thereby increasing cost. A tray with a rigid wall also prevents reduction of the tray""s volume prior to and/or after lyophilization. Since the product""s volume relative to that of the tray is small before lyophilization and even smaller after lyophilization, it leads to unnecessary storage expenses especially when the lyophilized product has to be stored in a freezer.
Prior art bags designed for lyophilization, utilizing a hydrophobic membrane as the top wall, were made without side walls and without ports. Thus, when filled with a solution and placed on a lyophilizer shelf, the bag would have a cross-section that is tear-shaped, see FIG. 1a. This shape of the prior art bags presents two drawbacks for lyophilization. First, the contacting surface of the bottom of the bag with the shelf is limited to the midsection, while the sides are raised above the shelf, see FIG. 1a. As a consequence, less than 50% of the bottom surface may be available for direct heat transfer between the shelf and the product during both the freezing cycle and lyophilization (heating) cycle. The tear shaped cross-section also results in a non-uniform thickness of the product being lyophilized, which may cause product damage due to non-uniform freezing. Also, inefficient use of the lyophilizer is evident from the thinner sections drying much faster than the thicker midsection, and the tear-shaped tray results in lower product volume per foot print. Secondly, flexible containers without sidewalls are more likely to have the product contacting the membrane, resulting in, the product freezing against the membrane; the product would then dry against and plug up the membrane. Plugging of the membrane would result in reduction of the lyophilization rate. Furthermore, the lack of ports limits the usefulness of such bags, or requires complicated and expensive procedures to maintain sterility prior to lyophilization and when the product is to be used. The prior art also requires a heat sealer to seal the container once filled with product.
In general, molecules leaving any point along the top of a frozen mass can be viewed as a solid angle or a cone with its peak being the point on the surface of the product and its base, the perimeter of the membrane. The rate of evaporation depends on that solid angle. If part of the roof is blocked, the degree of blockage is dependent on the solid angle defined by the point on the surface and the external perimeter of the block. It is also possible to raise the membranous roof xe2x80x9cfarxe2x80x9d above the product thereby decreasing the solid angle of blockage and increasing the chance of molecules xe2x80x9cseeingxe2x80x9d the hole. However, raising the roof above the product decreases the ratio of product volume to lyophilizer container volume, wasting valuable lyophilizer space and storage space. Therefore, lyophilization rate can be improved by assuring that the footprint of the membrane corresponds as close as possible to the footprint of the floor. Improvement in the prior art design, such as reducing or eliminating non-membrane area over the product to be lyophilized, would be welcomed.
The rapid treatment of injured or diseased troops may be facilitated with the use of adult mesenchymal stem cells (MSCs) to initiate rapidly the regeneration of many connective tissues, e.g., muscle, bone, cartilage, tendon, ligaments, etc. Currently, storage and delivery of these cells requires temperatures lower than xe2x88x92120xc2x0 C., which is impractical or impossible in the military environment. Similarly, biomatrices seeded with cultured chondrocytes enhance the quality of the articular cartilage repair tissue in traumatic knee injuries. Each of these applications requires the technology to process, store and reconstitute the final product even under battlefield conditions.
Many biological assays require standards, or controls for validation. Some standards come in ampoules and many have to be refrigerated or frozen. A packaging system that allows biological standards to be stabilized by desiccation or lyophilization to improve their shelf-life and/or reduce the need for cold storage would be welcomed. Such a package, formed into multicavity entity, with each cavity individually filled by identical product of specific dosage. Having a package where each cavity can be opened without affecting the product in the other cavities (similar to multi lozenge dispenser) would also be welcomed.
It is therefore the objective of the present invention to provide a lyophilization container for collecting, processing, freeze drying, storing, reconstituting and utilizing biological and/or pharmaceutical products preferably maintaining sterile conditions.
It is a primary object of the invention to provide a lyophilization container comprising of a compliant bottom, foldable sidewalls, and a hydrophobic membrane as a top wall. The container preferably is designed for blood products but is adoptable to other products that would benefit from the design features of the invention such as having a flat pliable bottom that conforms to the shape of the lyophilizer""s shelf that it is placed on, allowing heat transfer essentially across its entire bottom, providing a uniform thickness of product to be lyophilized that assures more uniform, safer, faster, and more efficient lyophilization process, as well as, achieving a greater product volume capacity for the same shelf area.
It is also the objective of the present invention to provide a lyophilization container with a hydrophobic membrane as a xe2x80x9croofxe2x80x9d that provides a fluid path for vapor but not for liquids while acting as a barrier to bacteria.
In addition, the present invention provides a lyophilization container with removable means to cover the hydrophobic xe2x80x9croofxe2x80x9d, said cover rendering said membrane inoperative until said means are removed, thereby protecting the membrane during any processing required before the lyophilization process.
Another objective of the present invention is to provide a lyophilization container with means to support the hydrophobic xe2x80x9croofxe2x80x9d from contacting the product during the lyophilization process.
Yet another objective of the present invention is to provide a lyophilization container with side ports that allow the user to introduce the rehydration solution and/or administer the rehydrated solution to the patient in a sterile manner.
It is also the objective of the present invention to provide a lyophilization container having a low profile and a high ratio of product volume to container volume as well as allow loading the product with minimal reduction in the membrane area available for lyophilization.
It is also the objective of the present invention to provide a lyophilization container that can be used as a rigid container but can also be collapsed prior to and post lyophilization thereby reducing storage costs. Further, the container may be expanded to the volume corresponding to the rehydrated product.
It is another objective of this invention to provide devices that would enhance the production, storage, shipping, and reconstitution of products (e.g. RBC, MSC) requiring long-term stabilization by lyophilization or desiccation. These include culture dishes as well as single or multiwell flasks modified to enhance heat transfer, maintain sterility, and allow controlled rehydration of the product by the end user. Modification may include a thinner floor, a more conductive floor, designs that provide intimate contact and a thermally conductive plate that provides more uniform temperature across the floor of the containers.
The force exerted by the weight of products with low volume but large surface area (e.g. cells adhering to the floor of a culture dish) may be insufficient to displace a compliant floor to form intimate contact with the shelf of a lyophilizer. It is therefore another objective of the present invention to provide culture dishes (e.g. Falcon #353801) or multiwell flasks (e.g. Falcon #353224) modified to enhance heat transfer between their floor and the shelf of the lyophilizer. These containers also incorporate hydrophobic membranes to allow water vapor transfer while maintaining sterility of the product.
It is another objective of the present invention to provide a multicavity container for drying by lyophilization or desiccation, with each cavity individually filled with an identical product of a specific dosage, and where each cavity can be separated from the other cavities and processed (i.e. rehydrated) without affecting the product in the other cavities (similar to multi lozenge dispenser).
Other innovative and useful features of the present invention will become apparent in the specification given below. It should be emphasized that the use of blood products as the lyophilized product in describing the invention is for descriptive purposes only and should not be taken as a limitation of the invention in any shape or form.